SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
An ultrasound nebuliser with variable delivery temperature and nebulisation volume was tested for particle size distribution, efficiency, and application in a clinical environment. The results obtained comply with our criteria for a general purpose radioaerosol generating system for use in evaluating various parameters of lung function.
Although it is common practice to digitize radionuclide images onto the finest matrix available, their low count densities and poor spatial resolution suggest that quite large pixels should be adequate. Observers find these large pixels visually obtrusive, but minification of the image can reduce this effect. Experiments reported here have investigated how minification (achieved by increasing viewing distance) affects the perceived quality of images digitized onto different sized matrices. Observers' subjective preference for different pixel sizes was measured at various viewing distances using clinical bone images as test patterns. An objective measure of image quality was made by comparing the detectability of computer-generated focal areas of increased activity both in simple noisy backgrounds and in clinical bone images. The results show that a 128 X 128 matrix is adequate when the image is 8 cm2 and is viewed from 1 and 2 m. A finer matrix failed to produce better results.
Monoclonal antibodies (MAbs), with high specificy and high affinity for their target antigens, can be utilized for delivery of agents such as radionuclides, enzymes, drugs, or toxins in vivo. However, the implementation of radiolabeled antibodies as "magic bullets" for detection and treatment of diseases such as cancer has required addressing several shortcomings of murine MAbs. These include their immunogenicity, sub-optimal targeting and pharmacokinetic properties, and practical issues of production and radiolabeling. Genetic engineering provides a powerful approach for redesigning antibodies for use in oncologic applications in vivo. Recombinant fragments have been produced that retain high affinity for target antigens, and display a combination of rapid, high-level tumor targeting with concomitant clearance from normal tissues and the circulation in animal models. An important first step was cloning and engineering of antibody heavy and light chain variable domains into single-chain Fvs (molecular weight, 25-27 kDa), in which the variable regions are joined via a synthetic linker peptide sequence. Although scFvs themselves showed limited tumor uptake in preclinical and clinical studies, they provide a useful building block for intermediate-sized recombinant fragments. Covalently linked dimers or non-covalent dimers of scFvs (also known as diabodies) show improved targeting and clearance properties due to their higher molecular weight (55 kDa) and increased avidity. Further gains can be made by generation of larger recombinant fragments, such as the minibody, an scFv-CH3 fusion protein that self-assembles into a bivalent dimer of 80 kDa. A systematic evaluation of scFv, diabody, minibody, and intact antibody (based on comparison of tumor uptakes, tumor:blood activity ratios, and calculation of an Imaging Figure of Merit) can form the basis for selection of combinations of recombinant fragments and radionuclides for imaging applications. Ease of engineering and expression, combined with novel specificities that will arise from advances in genomic and combinatorial approaches to target discovery, will usher in a new era of recombinant antibodies for biological imaging.
Cancer gene therapy that utilizes toxic transgene products requires strict transcriptional targeting to prevent adverse normal tissue effects. We report on the use of a promoter derived from the cyclin dependent kinase inhibitor, p21((WAF1)), to control transgene expression. We demonstrate that this promoter is relatively silent in normal cells (L132, FSK, HMEC-1) compared to the almost constitutive expression obtained in tumour cells (DU145, LNCaP, HT29 and MCF-7) of varying p53 status, a characteristic that will be important in gene therapy protocols. In addition, we found that the p21((WAF1)) promoter could be further induced by both external beam radiation (up to eight-fold in DU145 cells), intracellular-concentrated radionuclides ([(211)At]MABG) (up to 3.5-fold in SK-N-BE(2c) cells) and hypoxia (up to four-fold in DU145 cells). We have previously achieved significant radiosensitization of tumour cells both in vitro and in vivo by using inducible nitric oxide synthase (iNOS) gene therapy to generate the potent radiosensitizer, nitric oxide (NO(.-)). Here, we report that a clinically relevant schedule of p21((WAF1))-driven iNOS gene therapy significantly sensitized both p53 wild-type RIF-1 tumours and p53 mutant HT29 tumours to fractionated radiotherapy. Our data highlight the utility of this p21((WAF1))/iNOS-targeted approach.
Very little is known of the factors controlling soil-to-plant transfer of radionuclides in tropical environments. As part of an IAEA/FAO coordinated research project (CRP) designed to elucidate some of those factors, near-surface samples of two agricultural red-earth soils (Blain and Tippera) were collected from a study site in the Northern Territory. The climate is tropical monsoonal with crops being grown over the wet season from December to March/April. It is important to understand soil variables that may be related to this dramatic seasonality. In this investigation, soil redox state and microbial populations were assessed before and after the growing season with a view to generating hypotheses for future evaluation. The X-ray absorption near edge structure (XANES) technique was used to determine overall changes in the solid-state redox speciation of Fe and Mn in soils across the growing period. Fe speciation did not change but approximately 10% of the total Mn was oxidised from Mn(II) to Mn(III) and Mn(IV) in both soils between October 1999 and April 2000. An apparent disconnect between Fe and Mn was not unexpected given the >10 times higher concentration of Fe in the soils compared with Mn. These results have implications for the bioavailability of redox sensitive radionuclides such as Tc and Pu. Similarly, microbial population estimates were derived before and after the growing period. Total bacterial populations did not vary from 10(6) to 10(7) colonies per gram. Fungal populations increased over the growing season from 3-6 x 10(5) to 1-4 x 10(6) colonies per gram of soil. Fungi have the potential to decrease soil pH and hence increase the bioavailability of radionuclides such as Cs. In addition, fungi act to facilitate plant nutrition. This could lead to enhanced accumulation of nutrient analogues (e.g. Sr and Ra for Ca; Tc for Mn), but this effect may be masked by improved biomass production.
A computerized edge-detection method was developed to obtain radionuclide ventriculograms for analysis of left-ventricular ejection fraction and segmental wall motion from first-pass studies following i.v. injection of radionuclide. The accuracy of this technique was examined in 21 patients undergoing cardiac catheterization. Tc-99m DTPA was injected into an antecubital vein, with data acquisition in the 30 degrees RAO projection by a gamma scintillation camera interfaced to a computer. A computerized profile analysis was used to determine objectively the edge of the left-ventricular blood pool. Time-activity curves were generated, and the ejection fraction was calculated from sequential end-diastolic and end-systolic count rates. The values for ejection fraction correlated well with those obtained by single-plane contrast ventriculography (r = 0.95). End-diastolic and end-systolic images were reconstructed from the time-activity curve. To analyze segmental wall motion, the left-ventricular outline was divided into five segments and the motion of each segment was graded qualitatively from 1 to 5. Seventy-five of 105 segments had the same grade as the wall motion determined by contrast angiography, and 102 of 105 were within one grade. (P less than 0.001). These findings demonstrate the accuracy of this improved technique for objective, rapid, and noninvasive determination of left-ventricular function.
We studied the acute effects of nisoldipine, a new second-generation calcium channel-blocking drug, on cardiac hemodynamics and left ventricular (LV) contractility in 10 patients with grade 2 to 4 cardiac failure. Pressures were measured from an arterial line and a flow-guided catheter in the pulmonary artery, cardiac output by thermodilution, and LV ejection fraction simultaneously by radionuclide ventriculography. Ventricular loading conditions were altered by sublingual nitroglycerin to facilitate construction of LV end-systolic pressure (radial stress)-volume and stress-shortening curves. Nisoldipine, given by continuous intravenous infusion (0.12 micrograms/kg/min), reduced mean arterial pressure (p = 0.001), systemic vascular resistance (p less than 0.05), and the double product, a measurement of myocardial oxygen demand (p less than 0.01). Cardiac index, stroke index, and LV ejection fraction increased in 8 of the 10 patients. LV contractility was initially greatly reduced and was unchanged or slightly decreased during the administration of nisoldipine. Emax, the slope of the end-systolic pressure-volume curve, was unaltered in half of the patients and decreased in the others (NS), whereas the end-systolic stress-shortening curve did not change. In summary, nisoldipine has a potentially useful acute hemodynamic profile in patients with cardiac failure; it increases forward blood flow in most patients, decreases the determinants of myocardial oxygen demand, and produces little measurable changes in the inotropic state of the left ventricle.
Computer generation of functional images has gained recognition as a valuable method of analyzing physiologic data. However, most mathematical models used to produce these images are frequency-based, which requires that the entire function be examined. Because frequency-based characteristics are only indirectly related to physiologic characteristics, this technique has inherent deficiencies that may be minimized through various manipulations. Our technique is to base such images on time-related features, rather than frequency-based. This technique deals directly with regional count rate behavior, which in turn reflects function. Benefits from such an approach include the ability to generate images from isolated portions of an event and the removal of sinusoidal models that may or may not accurately represent function. Our experience with such an approach to the generation of functional images of the heart, lungs, and liver has been highly successful.
A folate-receptor-targeting radiopharmaceutical, Ga(III)-deferoxamine-folate (Ga-DF-Folate), was radiolabeled with two positron-emitting isotopes of gallium, cyclotron-produced (66)Ga (9.5 hour half-life) and generator-produced (68)Ga (68 minute half-life). The [(66)Ga]Ga-DF-Folate was administered to athymic mice with folate-receptor-positive human KB cell tumor xenografts to demonstrate that microPET mouse tumor imaging is feasible with (66)Ga, despite the relatively high positron energy of this radionuclide. Using the athymic mouse KB tumor xenograft model, dual-isotope autoradiography was also performed following i.v. co-administration of [(18)F]-FDG, a marker of regional metabolic activity, and folate-receptor-targeted [(111)In]In-DTPA-Folate. The autoradiographic images of 1 mm tumor sections demonstrate the gross heterogeneity of the KB cell tumor xenograft, as well as subtle disparity in the regional accumulation of the two radiotracers.
OBJECTIVE: Radiation dose to the testes from radionuclide therapies is of concern. This study evaluated image-quantification methods for testicular uptake in a phantom and in patients. METHODS: A 50-mL vial and a large water tank were used to simulate testes and the body, respectively. Activity concentration in the vial and water tank was prepared to generate testes-to-background concentrations of 1.3 and 1.1. Five male lymphoma patients who received a Zevalin (Biogen Idec, Cambridge, MA) regimen and 6 male colorectal cancer patients who received a Pretarget (Neo Rx, Seattle, WA) CC49Fusion protein were evaluated. Testicular activity was quantified using two methods: (1) geometric-mean, background-corrected testicular region of interest (ROI) counts as a fraction of body counts without explicit attenuation correction (Zevalin Kit); (2) background-corrected anterior testicular ROI counts with attenuation correction using known depth in the phantom and CT depth in patients. RESULTS: In the phantom study, Method 1 underestimated 49% and 39%, at image contrast of 1.3 and 1.1, respectively. Quantification was improved using Method 2 (7% for a 1.3 contrast, -17% for a 1.1 contrast). Method 2 was used in patients because background-corrected posterior ROI counts were statistically unreliable due to poor image contrast. In patients receiving Zevalin, the median peak percent injected dose (%ID)/testis was 0.10 (range, 0.08-0.18) with a median biologic half-time (T(bio1/2)) of 156 (range, 91-4200) hours. The median dose was 2.4 (range, 1.5-3.6) Gy/GBq, compared to the originally reported mean dose of 9.1 (range, 5.4-11.4) Gy/GBq (Zevalin package insert). In patients receiving the Pretarget CC49Fusion protein, the median peak %ID/testis was 0.22 (range, 0.05-0.29) with a median T(bio1/2) of 44 (range, 37-64) hours. The median dose was 0.84 (range, 0.3-1.2) Gy/GBq. CONCLUSION: This study found that testicular doses from Zevalin were much lower than that originally reported in the package insert. The median testicular dose from Pretarget CC49Fusion protein was less than half that of the median testicular dose from Zevalin.
The current role of nuclear medicine in clinical diagnosis was surveyed in a retrospective review of medical records by two internists. About one radiologic imaging study in 20 was a radionuclide procedure, and a somewhat larger fraction was performed in outpatients. The internists found that diagnostic screening procedures in nuclear medicine influenced patient management in 63% of hospital inpatients, and quantitative/monitoring types of tests influenced management in 56%. Of the projected health care costs in the United States of $490 billion, all imaging procedures will account for only $12 billion, and nuclear medicine procedures will account for about $1 billion. Nuclear medicine research continues to blossom. The National Institutes of Health budget for diagnostic imaging research in fiscal year 1988 totaled $86.6 million; nuclear medicine projects represented 43% of this total, all other projects in radiology represented 30%, and projects outside radiology represented 30%. Research with positron emitters and positron emission tomography totaled $20.5 million, and research with radiolabeled monoclonal antibodies totaled $6.2 million. Two major problems may hinder the future practice of nuclear medicine in the United States compared with that in other developed countries: (a) the serious time lag in the approval process for new radiopharmaceuticals by the U.S. Food and Drug Administration and other agencies and (b) the lack of a facility dedicated to the continuous production of radionuclides for biomedical research. Now, there is sporadic production permitted only during high-energy physics experiments. The recent developments which will probably induce the greatest changes in clinical nuclear medicine in the near future are the improvements in design and utilization of single photon emission computed tomographic devices and prolific generation of new radiopharmaceuticals, especially technetium-99m agents for cerebral and myocardial imaging and tumor agents.
We have shown that natural drosophila populations from the settlement Vetka of Gomel region with increased radiation background are more adapted to mutagenic effect of radiation than drosophila populations from Berezinsky reserve (the control). After the populations were placed into laboratory thermostat adaptation of Vetka population remained within 6-8 generations without irradiation. However the control population became more resistant too. So, the keeping of natural drosophila populations under laboratory conditions was a stress and led to unspecific adaptation the same as a low level of radiocontamination did. These facts should be considered in studying dynamics of the mutation level during radionuclide removal in animals caught in radiocontaminated regions and placed in vivaria conditions.
UNLABELLED: Radiolabeled peptides are of increasing interest in nuclear oncology. Special emphasis has been given to the development of peptides labeled with positron emitters. Among these, (68)Ga deserves special attention, because it is available from an inhouse generator rendering (68)Ga radiopharmacy independent of an onsite cyclotron. (68)Ga has a half-life of 68 min and decays by 89% through positron emission. The parent, (68)Ge, is accelerator produced and decays with a half-life of 270.8 d by electron capture. Currently, at least 1 commercial and several in-house generators are available. (68)Ge is strongly absorbed on metal oxides or organic material, making a (68)Ge-breakthrough highly unlikely. Several groups continue to further develop generators to remove cationic impurities from the eluate. Several bifunctional chelators based on 1,4,7-triazacyclononane-N,N',N''-triacetic acid and 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) macrocycles are available for coupling to peptides and other biomolecules. In addition to these hydrophilic chelators, a lipophilic tetradentate S(3)N ligand was developed. Radiopeptides for (68)Ga labeling have been developed and tested preclinically for the targeting of somatostatin receptors, the melanocortin 1 receptor, and the bombesin receptor. Clinical studies were performed with (68)Ga-DOTA,Tyr(3)-octreotide, localizing neuroendocrine tumors with higher sensitivity than (111)In-diethylenetriaminepentaacetic acid-octreotide. In addition, (68)Ga-DOTA-based bombesin derivatives are being investigated with some success in patients with prostate cancer. CONCLUSION: Generator-produced (68)Ga and the development of small chelator-coupled peptides (and other small biomolecules) may open a new generation of freeze-dried, good manufacturing practice-produced, kit-formulated PET radiopharmaceuticals similar to (99)Mo-/(99m)Tc-generator-based, (99m)Tc-labeled radiopharmaceuticals.
Using a radiolabelled bran preparation, a large field of view gamma-camera and a computer, a method has been developed to define and analyse the gastrointestinal transit profile of solids. Unprocessed bran, labelled with technetium (99mTc) sulphur colloid is incorporated into biscuits cooked in a microwave oven. With this preparation, less than 3.4% of the isotope dissociated from the bran in a gastric milieu, and more than 90% of recovered radionuclide activity, were retained with the solid phase during small intestinal transit in subjects with stable ileostomy function. A normal range for gastric emptying (GE), small intestinal transit (IT) and colonic filling (CF) was established in 15 healthy volunteers. Anterior and posterior images were taken until all isotope was present in the colon. Using regions of interest for the stomach and colon, decay corrected geometric mean curves for GE and CF were generated. GE was characterized by a lag phase followed by a linear emptying phase. The GE profile (mean and standard deviation) was described by 'power exponential' parameters of half-emptying time (1.6 +/- 0.4 h) and beta (1.5 +/- 0.2). The IT time was 3.9 +/- 1.5 h. The onset of CF was determined visually (4.1 +/- 1.5 h), and the time of 50% CF filling was determined from the colonic filling curve (5.5 +/- 1.4 h). This technique should provide a useful, practical, clinical and research test to study the pathophysiology and pharmacology of intestinal motor disorders.
A limitation of first-pass radionuclide angiocardiography is the limited repeatability because of the relatively long half-life of technetium-99m (Tc-99m). The feasibility, reproducibility and validity of multiple sequential quantitative first-pass studies were assessed in humans using the short-lived isotope gold-195m (Au-195m) (half-life of 30.6 seconds, 262 keV), which can be directly obtained from a generator made of its parent isotope, mercury-195m (half-life of 41.6 hours). Thirty-three subjects (13 normal volunteers and 20 cardiac patients) were studied using a large-field gamma camera equipped with a medium-energy collimator. After Au-195m intravenous injections, repeat first-pass studies were performed in the left anterior oblique projection. A left anterior oblique study was then obtained after i.v. injection of Tc-99m. Left ventricular ejection fraction calculations were performed separately by 2 observers. Reproducibility of Au-195m first-pass studies was excellent. The correlation coefficients for left ventricular ejection fraction from the first and the second Au-195m injections were 0.93 and 0.98 for observers 1 and 2, respectively. The correlation coefficients between Au-195m and Tc-99m first-pass studies were 0.95 and 0.98, respectively.
There can be little doubt that one of the most important problems in the management of cancer is control of metastatic disease. This objective must be achieved ideally with a systemic therapeutic modality that targets cancer cells and gives minimal collateral damage to critical normal cells. The efficacy of targeted cancer therapy relies on the ability of a toxin to be located in the target cancer cell. The ideal toxin is one that is active only in the cancer cell, and not in critical normal cells. Failing this, the next best approach is a toxin with a short effective lifetime to target early stage micrometastatic disease. This rules out chemical toxins, given that they remain effective until excreted from the body, and localization of dose to the cancer cell rules out beta-emitting radio-isotopes (RI). Alpha-emitting RI, however, are much more appropriate toxins because they are short-lived and because their cytotoxicity is the result of their high rate of energy loss and short range of the alpha particles. These radionuclides have properties that are particularly suited for the elimination of single cells in transit or small nests of cancer cells. In vitro and in vivo experiments with alpha RI show dramatic superiority over beta RI. Only a few nuclear hits are needed to kill cells, and the formation of metastatic lung lesions and subcutaneous lesions in mice can be inhibited by systemic administration of alpha emitters. But alpha RI have not been able to control solid tumours, for which beta RI are better suited. A small number of alpha-emitting radionuclides are currently under investigation. These are terbium (Tb)-149, astatine (At)-211, bismuth (Bi)-212 and Bi-213. Terbium-149 and At-211 both require accelerators in close proximity to the place of application. The Bi isotopes are produced by long-lived parents and, as such, can be obtained from generators. The first phase-1 dose escalation trial with Bi-213 radioimmunoconjugate (RIC) commenced in New York in 1997, and other trials are planned with At-211 RIC and At-211 methylene blue for melanoma. Actinium (Ac)-225 is obtained from the decay of thorium (Th)-229, which is a waste product in the enrichment of fissile Th-233. Alternative accelerator production routes are being investigated, beginning with the European Centre for Nuclear Research (CERN) GeV proton spallation source. The ready and low-cost availability of the Ac:Bi generator is an important element in the implementation of clinical trials for patients with poor prognoses but without evidence of metastatic disease.
Tracheobronchial circulation during exercise has previously not been examined. Therefore blood flow to the trachea and bronchi (up to 7th generation of branching) was studied in seven healthy adult ponies at rest and during the 3rd and 10th min of exercise performed at a treadmill speed setting of 25 km/h. The ambient air temperature varied from 19 to 20 degrees C and humidity from 35 to 45%. To determine blood flow radionuclide-labeled 15-microns-diameter microspheres were injected into the left ventricle via a catheter advanced from the left carotid artery (exposed using local anesthesia), and a reference sample was obtained from the aorta. Adequate mixing of microspheres with blood was demonstrated by similar perfusion values for left and right kidneys. Exercise increased heart rate (194 +/- 9 and 200 +/- 7 beats/min) and mean aortic pressure (169 +/- 8 and 156 +/- 4 mmHg) of ponies at 3rd and 10th min. Tracheal blood flow (6.7 +/- 0.5 ml.min-1 x 100 g-1) of resting ponies was only one-third of the bronchial blood flow (21.6 +/- 4.9 ml.min-1 x 100 g-1) Significant changes in tracheal perfusion did not occur at 3rd or 10th min of exercise. Although bronchial perfusion also did not change at the 3rd min of exercise, it rose dramatically to 202.8 +/- 30.3 ml.min-1 x 100 g-1 during the 10th min. Concomitantly, renal blood flow decreased at 10th min of exertion. The large increase in bronchial blood flow at 10th min of exertion may have been necessitated by the need to help dissipate body heat.
Since technetium-99m (99mTc) was introduced in medical research it has become one of the most employed radionuclides in nuclear medicine. 99mTc is ideal for routine use on the labeling of different radiopharmaceuticals due to its favorable characteristics. However, some biological effects have been described. These effects may be related to internal conversion electron and/or Auger electron emissions from 99mTc decay that present high linear energy transfer and can generate reactive oxygen species (ROS) in the medium. We evaluated in Escherichia coli K12S and Salmonella typhimurium TA102, both proficient in DNA repair, contribution of those decay emissions on the cytotoxicity induced by 99mTc, both either by generating lesions on DNA or by inducing alterations at membrane. We also studied the genotoxic and/or mutagenic potentiality of 99mTc, in Salmonella typhimurium, using the Ames test. The results showed that: i/ 99mTc is cytotoxic to the Escherichia coli K12S strains; ii/ this effect is related to the electrons (Auger and internal conversion) emissions, and iii/ the 99mTc is not mutagenic and/or genotoxic, when measured by Ames test.